CN115515958B - Novel sulfonamide (Menin-MLL) interaction inhibitor, preparation method and medical application thereof - Google Patents

Novel sulfonamide (Menin-MLL) interaction inhibitor, preparation method and medical application thereof Download PDF

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CN115515958B
CN115515958B CN202280003521.5A CN202280003521A CN115515958B CN 115515958 B CN115515958 B CN 115515958B CN 202280003521 A CN202280003521 A CN 202280003521A CN 115515958 B CN115515958 B CN 115515958B
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compound
leukemia
mll
ethyl
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CN115515958A (en
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祝辉
王健航
赵杰斌
吴先强
陈洪
王颖
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Chengdu Easton Biopharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

Compounds of formula (I), pharmaceutically acceptable salts thereof, and methods for their preparation and use are provided. The compounds are useful as agents in the treatment of diseases and conditions, including cancer, other diseases mediated by the men-MLL interaction.

Description

Novel sulfonamide (Menin-MLL) interaction inhibitor, preparation method and medical application thereof
Technical Field
The application belongs to the technical field of biological medicines, and particularly relates to a novel sulfonamide (men-MLL) interaction inhibitor, a preparation method and medical application thereof.
Background
Mixed lineage leukemia rearrangement (mixed lineage leukemia-rearranged, MLL-r) is an acute leukemia with a poor prognosis, caused by spontaneous translocation of the MLL1 gene. The translocation-generated MLL-r fusion protein binds with high affinity to the nucleoprotein Menin, which interacts with the MLL to cause leukemia to occur by driving specific transcription programs.
There is currently no Acute Myelogenous Leukemia (AML) drug or therapy cohort for MLL-r or NPM1 mutations, the presence of MLL fusion proteins is a sign of poor prognosis of leukemia, MLL-r leukemia patients respond poorly to currently available therapies, and overall survival rates for 5 years are approximately 35%; translocation of the MLL gene is associated with a 13-34% reduction in the 5 year disease-free survival of children, with an average five year survival of only 5-10% for AML adult patients with MLL-r. The overall survival rate of NPM1 mutant AML was about 50% for 5 years. In addition, AML recurrence rates are high, with about 50% of patients relapsing within 1-2 years, and most of the relapsed AML eventually turns into relapsed/refractory AML, for which no effective treatment regimen exists. AML presents a large molecular heterogeneity and patients carrying different mutations may have distinct prognosis. The direction of AML drug development is to more accurately target different mutations and develop targeted drugs for different mutations.
A Menin-MLL interaction inhibitor belongs to an epigenetic inhibitor and can block the interaction of the MLL fusion protein (MLL-r) in the cells of the Menin and leukemia. There are currently 2 compounds in clinical research, SNDX-5613 is conducting a clinical phase 1/2 study for patients with recurrent/refractory acute leukemia carrying MLL rearrangements or NPM1 mutations, KO-539 is conducting a clinical phase 1 study for patients with recurrent/refractory acute leukemia carrying MLL rearrangements or NPM1 mutations.
In conclusion, the Menin-MLL interaction inhibitor has good application prospect as a drug research and development, and has good clinical requirements for developing a novel high-efficiency low-toxicity Menin-MLL interaction inhibitor.
Disclosure of Invention
The present application provides a compound of formula (i), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
a is selected from C 6 -C 10 Aryl or C 4 -C 10 Heteroaryl, which may be independently substituted by R 1 、R 2 Or R is 3 Substitution;
b is selected from C 4 -C 8 Cycloalkyl, C 6 -C 10 Aryl, C 5 -C 10 Heteroaryl, said cycloalkyl, aryl, heteroaryl being independently substituted by R b1 Or R is b2 Substitution;
l is selected from C 3 -C 10 A heteromonocyclic amine, a bicyclic amine, a bridged cyclic amine, or a spiro amine;
q is selected from-C (R) q1 R q2 ) -, -C (=o) -, -S (=o) -or-S (=o) 2 -；
X is selected from-O-, -CR x1 R x2 or-NR x1 R x2 ；
R x1 、R x2 Each independently selected from H, C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl;
R q1 、R q2 each independently selected from H or C 1 -C 6 An alkyl group;
R b1 、R b2 each independently selected from H, -OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy or C 1 -C 3 A haloalkyl group;
R 1 、R 2 、R 3 each independently selected from H, -OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, -C (O) NR 1a R 2a 、-S(O)NR 1a R 2a 、-S(O) 2 NR 1a R 2a 、-C(O)R 1a 、-S(O) 2 R 1a 、-NR 1a S(O)R 2a 、-NR 1a S(O) 2 R 2a 、-NR 1a C(O)R 2a 、C 6 -C 10 Aryl, 5-7 membered heteroaryl, C 3 -C 8 Cycloalkyl or 3-8 membered heterocyclyl, wherein C 6 -C 10 Aryl, 5-7 membered heteroaryl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclyl may optionally be substituted with one or more-OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy or C 1 -C 6 Haloalkyl substitution; r is R 1a 、R 2a Each at each occurrence is independently selected from H, C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl;
rm, rn are independently selected from H, -OH, halogen, cyano, amino, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, C 1 -C 3 Cyanoalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Hydroxyalkyl, -C (O) NR 1b R 2b or-NR 1b C(O)R 2b ；R 1b 、R 2b Each at each occurrence is independently selected from H or C 1 -C 6 An alkyl group;
n is 1, 2, 3 or 4.
It is another object of the present application to provide a compound of the structure of formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof,
wherein A is selected from C 6 -C 10 Aryl or 5-10 membered heteroaryl, which aryl or heteroaryl may be independently substituted by R 1 、R 2 Or R is 3 Substitution;
b is selected from C 4 -C 8 Cycloalkyl, C 6 -C 10 Aryl or 5-10 membered heteroaryl, which cycloalkyl, aryl or heteroaryl may be independently substituted by R b1 Or R is b2 Substitution;
l is selected from 4-10 membered heteromonocyclic amine, parallel cyclic amine, bridged cyclic amine or spiro cyclic amine;
q is selected from-C (R) q1 R q2 ) -, -C (=o) -, -S (=o) -or-S (=o) 2 -；
X is selected from-O-, -CR x1 R x2 or-NR x1 R x2 ；
R x1 、R x2 Each independently selected from H, C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl;
R q1 、R q2 each independently selected from H or C 1 -C 6 An alkyl group;
R b1 、R b2 each independently selected from H, -OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy or C 1 -C 3 A haloalkyl group;
R 1 、R 2 、R 3 each independently selected from H, -OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, -C (O) NR 1a R 2a 、-S(O)NR 1a R 2a 、-S(O) 2 NR 1a R 2a 、-C(O)R 1a 、-S(O) 2 R 1a 、-NR 1a S(O)R 2a 、-NR 1a S(O) 2 R 2a 、-NR 1a C(O)R 2a 、C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 8 Cycloalkyl or 4-8 membered heterocycloalkyl, wherein C 6 -C 10 Aryl, 510 membered heteroaryl, C 3 -C 8 Cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted with one or more-OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy or C 1 -C 6 Haloalkyl substitution; r is R 1a 、R 2a Each at each occurrence is independently selected from H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-6 membered heterocycloalkyl;
rm, rn are independently selected from H, -OH, halogen, cyano, amino, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, C 1 -C 3 Cyanoalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Hydroxyalkyl, -C (O) NR 1b R 2b or-NR 1b C(O)R 2b ；R 1b 、R 2b Each at each occurrence is independently selected from H or C 1 -C 6 An alkyl group;
n is 1, 2, 3 or 4.
In certain preferred embodiments, a is selected from substituted or unsubstituted phenyl, naphthyl, thiophene, or pyridine.
In certain more preferred embodiments, a is selected from substituted or unsubstituted phenyl or thiophene.
In certain more preferred embodiments, the compound of formula (i) or an optical isomer thereof has a structure shown in Ia, ib, ic, id:
wherein L is selected from 4-10 membered heteromonocyclic amine, parallel cyclic amine, bridged cyclic amine or spiro cyclic amine;
q is selected from-C (R) q1 R q2 ) -, -C (=o) -, -S (=o) -or-S (=o) 2 -；
X is selected from-O-, -CR x1 R x2 or-NR x1 R x2 ；
R x1 、R x2 Each independently selected from H, C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl;
R q1 、R q2 each independently selected from H or C 1 -C 6 An alkyl group;
R b1 、R b2 each independently selected from H, -OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy or C 1 -C 3 A haloalkyl group;
R 1 、R 2 、R 3 each independently selected from H, -OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, -C (O) NR 1a R 2a 、-S(O)NR 1a R 2a 、-S(O) 2 NR 1a R 2a 、-C(O)R 1a 、-S(O) 2 R 1a 、-NR 1a S(O)R 2a 、-NR 1a S(O) 2 R 2a 、-NR 1a C(O)R 2a 、C 6 -C 10 Aryl, 5-7 membered heteroaryl, C 3-8 Cycloalkyl or 4-8 membered heterocycloalkyl, wherein C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 8 Cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted with one or more-OH, halogen, cyano, C 1 -C 6 Alkyl, C 1 -C 3 Alkoxy or C 1 -C 6 Haloalkyl substitution; r is R 1a 、R 2a Each at each occurrence is independently selected from H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl or 4-6 membered heterocycloalkyl;
rm, rn are independently selected from H, -OH, halogen, cyano, amino, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, C 1 -C 3 Cyanoalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Hydroxyalkyl, -C (O) NR 1b R 2b or-NR 1b C(O)R 2b ；R 1b 、R 2b Each at each occurrence is independently selected from H or C 1 -C 6 An alkyl group;
n is 1, 2, 3 or 4.
As a preferred embodiment, B is selected from C 4 -C 8 Cycloalkyl groups.
In certain preferred embodiments, L is selected from:
in certain more preferred embodiments, L is selected from:
wherein, the p end is connected with pyrimidinyl, and the Q end is connected with Q.
In certain preferred embodiments, Q is-CH 2 。
In certain preferred embodiments, R 1 、R 2 、R 3 Each independently selected from H, halogen, -C (O) NR 1a R 2a Or a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl may optionally be substituted with one or more C 1 -C 6 Alkyl substitution; r is R 1a 、R 2a Each at each occurrence is independently selected from H or C 1 -C 3 An alkyl group;
in certain more preferred embodiments, R 1 、R 2 、R 3 Each independently selected from H, fluorine, chlorine, bromine, iodine,
In certain preferred embodiments, rm, rn are each independently at each occurrence selected from H, -OH, halogen, cyano, amino, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, C 1 -C 3 Cyanoalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Hydroxyalkyl, -C (O) NR 1b R 2b or-NR 1b C(O)R 2b ；
In certain more preferred embodiments, rm, rn are independently selected from H, -OH, F, cl, cyano, amino, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, C 1 -C 3 Cyanoalkyl, C 1 -C 3 Hydroxyalkyl or-C (O) NH 2 ；
In certain more preferred embodiments, n is 1, 2 or 3.
In certain preferred embodiments, the compound is selected from the group consisting of:
the compounds of the present application may be prepared in the form of pharmaceutically acceptable salts, including organic acid salts and inorganic acid salts thereof, including but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, biphosphoric acid, hydrobromic acid, hydroiodic acid, and the like, and organic acids including but not limited to acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid salts, maleic acid, citric acid, fumaric acid, tartaric acid, succinic acid, malic acid, camphoric acid, nicotinic acid, salicylic acid, oxalic acid, lactic acid, and the like, according to conventional methods.
In another aspect, the present application also provides a process for the preparation of a compound of formula (I), including but not limited to:
(1) Scheme 1:
therein, A, B, L, Q, X, R m 、R n And n is as defined above;
PG is a protecting group selected from: cbz, boc, fmoc, alloc, teoc, etc.;
LVG is a leaving group selected from: -I, -Br, -Cl, msO-, tfO-, tsO-, etc.;
1) The raw material S1 reacts with the raw material S2 to generate a compound I-1;
2) The compound I-1 is subjected to an oxynitrides reaction to generate a compound I-2;
3) Carrying out halogenation reaction on the compound I-2 to generate a compound I-3;
4) Removing protecting groups after the compound I-3 reacts with the compound PG-L-H to generate a compound I-4;
5) Reacting the compound I-4 with an intermediate M1, and removing Boc protection to obtain an intermediate I-5;
6) Reacting the compound I-5 with a reagent M2 to obtain a compound shown in a formula (I);
(2) Scheme 2:
therein, A, B, L, Q, X, R m 、R n And n is as defined in any one of claims 1 to 9; the process for preparing compound I-3 is the same as that of scheme 1; the obtained compound I-3 directly reacts with an intermediate M3 to obtain an I-5 compound, and then reacts with a reagent M2 to obtain the compound shown in the formula (I).
In another aspect, the present application also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a disease associated with the men-MLL protein.
Specifically, the disease related to the men-MLL protein refers to mixed leukemia (MLL), MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed leukemia (MLL-r), leukemia related to MLL rearrangement or MLL gene rearrangement, acute leukemia, chronic leukemia, lymphoblastic leukemia, myelogenous leukemia, childhood leukemia, acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), acute myelogenous leukemia, acute non-lymphoblastic leukemia, chronic Lymphoblastic Leukemia (CLL), chronic Myelogenous Leukemia (CML), leukemia related to treatment, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), myeloproliferative neoplasia (MPN), plasma cell tumor, multiple myeloma, myelodysplasia, cutaneous T cell lymphoma, lymphoid tumor, hairy cell leukemia, leukemia meningitis, multiple myeloma, hodgkin's lymphoma, and non-malignant lymphoma.
The application discovers that a novel structure of the men-MLL interaction inhibitor has a structure shown as a formula (I) compound, has good cell inhibition activity and good pharmacokinetic property, and is a new generation of high-efficiency low-toxicity men-MLL interaction inhibitor.
Detailed Description
The following description of the technical solutions in the embodiments of the present application will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
Definition and general description:
unless otherwise indicated, the terms used in the present application have the following meanings. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The compounds and derivatives provided in the present application may be named according to IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
Definition of terms used in connection with the present application: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"substituted" means that a hydrogen atom in the molecule is replaced with a different atom or group; or the lone pair of atoms in the molecule being replaced by other atoms or groups, e.g. the lone pair on the S atom may be replaced by an O atom
"optionally further substituted" means that "substitution" may, but need not, occur, and that the description includes situations that occur or do not, i.e., substituted or unsubstituted.
"alkyl" refers to a saturated hydrocarbon group consisting of only carbon and hydrogen atoms, with single bonds between carbon and carbon, and between hydrocarbon, and the alkyl group may be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of other groups which may be alkoxy, cyanoalkyl, aminoalkyl, hydroxyalkyl, etc.
"cycloalkyl" refers to a carbocycle that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, cycloalkyl groups herein may be C 3 -C 8 For example a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring or an 8-membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
"heterocyclyl" refers to heterocycloalkyl; heterocycloalkyl means a saturated or non-aromatic partially saturated ring with a single ring or multiple rings (fused, bridged, spiro) containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. Typically a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system of ring atoms comprising 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
"aryl" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl is typically a monocyclic, bicyclic or tricyclic aryl group having multiple carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings fused together.
"heteroaryl" is an aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. An aromatic mono-or bicyclic hydrocarbon typically comprising a plurality of ring atoms, wherein one or more of the ring atoms is selected from heteroatoms of O, N, S. Preferably comprising one to three heteroatoms. Heteroaryl represents, for example: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, and the like.
"halogen" means fluorine, chlorine, bromine or iodine.
"cyano" refers to-CN.
"haloalkyl" refers to an alkyl group as defined above substituted with one or more, preferably 1-5 (e.g., 1, 2, 3, 4, or 5) halogen atoms. Haloalkyl includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and the like, such as chloromethyl, dichloromethyl, difluoromethyl, dibromomethyl, trifluoromethyl, 2-trifluoroethyl, perfluoroethyl, 2-trifluoro-1, 1-dichloroethyl, and the like.
"alkoxy" refers to an-O-alkyl group.
"haloalkoxy" refers to an alkoxy (-O-alkyl) group as defined above substituted with one or more, preferably 1-5 (e.g., 1, 2, 3, 4, or 5) halogen atoms.
"cyanoalkyl" means that one hydrogen atom on the alkyl group is replaced with a cyano group.
"aminoalkyl" means an alkyl group wherein one hydrogen atom has been replaced by an amino group.
A hydrogen atom on a "hydroxyalkyl" alkyl group is replaced with a hydroxy group.
“C m-n Heteroaryl "refers to aryl groups containing other heteroatoms, wherein the number of carbon atoms and heteroatoms involved in the ring may be m-n (n is greater than m and both are integers).
In this context, unless otherwise indicatedDescription, the term "C" is used m -C n "means that the moiety modified by the term has m-n carbon atoms (n is greater than m and both are integers). For example, C 1 -C 6 Representing that the modified moiety has 1-6 carbon atoms, for example 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
"m-n membered (hetero) cyclic hydrocarbon group" means the number of hetero atoms having m-n carbon atoms and participating in ring formation in the moiety modified by the term, and the hetero atoms may be nitrogen atoms, sulfur atoms, oxygen atoms or the like (n is larger than m and both are integers). For example, a 4-8 membered cyclic olefin means that it has 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms or carbon atoms in its modified ring structure; the 4-10 membered heterocyclic hydrocarbon group means that the number of carbon atoms and hetero atoms contained in the modified ring structure thereof is 4, 5, 6, 7, 8,9 or 10.
In the present application, when chemical names and structural formulas are not identical, the structural formulas should be referred to unless it is inferred that the chemical names are not the structural formulas are correct as context may be.
The structure of the compound is characterized by Mass Spectrum (MS) or nuclear magnetic resonance 1 HNMR).
Nuclear magnetic resonance hydrogen spectrum [ ] 1 HNMR) is determined by using Bruker AVANCE-400 nuclear magnetic resonance apparatus, the determination solvent is deuterated dimethyl sulfoxide (DMSO), the internal standard is Tetramethylsilane (TMS), and the chemical shift is 10 -6 (ppm) is given as a unit.
The Mass Spectrum (MS) was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: therm, model: finnigan LCQ advantage MAX).
The thin silica gel layer is prepared from tobacco stage yellow sea HSGF254 or Qingdao GF254 silica gel plate.
Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
In the terms of the present application, "nitrogen protection" means, for example, connecting the reaction flask to a 1L volume nitrogen balloon.
In the case where no specific explanation is given to the present application, the solution mentioned in the reaction of the present application is an aqueous solution.
The term "room temperature" in the present application means that the temperature is between 10℃and 25 ℃.
Example 1N-Ethyl-5-fluoro-N-isopropyl-2- ((4- (7- (((1 r,4 r) -4- (pyrroline-1-sulfonylamino) cyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) benzamide (1)
The synthetic route is as follows:
step 1N-Ethyl-5-fluoro-N-isopropyl-2- (pyrimidin-5-yloxy) benzamide (1-1)
N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (12.54 g,54.6 mmol), 5-bromopyrimidine (25.3 g,156.0 mmol), cesium carbonate (77.8 g,234.0 mmol) were dissolved in anhydrous DMF and reacted at 130℃for 16h. TLC detection (P/e=2/1) reaction was completed, cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was recovered by rotary evaporation, and purified by column chromatography to isolate (P/e=8/1 to 2/1) to give 27.6g (yield: 56.6%) of a yellow oily product. ESI-MS m/z 304.2[ M+H ]] + 。
Step 2 5- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) pyrimidine-1-oxynitride (1-2)
The above intermediate 1-1 (27.2 g,87.9 mmol) was dissolved in anhydrous dichloromethane, m-CPBA (46.46 g,263.8 mmol) was added under ice-bath, the reaction was carried out overnight at room temperature, LC/MS detection was completed, the reaction solution was washed 1 time with saturated sodium sulfite solution, saturated sodium bicarbonate solution was washed 2 times, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was recovered by rotary evaporation to give 24.1g (yield: 83.3%) of crude yellow oily product. ESI-MS m/z 320.2[ M+H ]] + 。
Step 3 2- ((4-Chloropyrimidin-5-yl) oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-3)
The above intermediate 1-2 (23.8 g,73.1 mmol) was dissolved in chloroform, triethylamine (15.7 ml,109.6 mmol) and phosphorus oxychloride (12.5 ml,131.6 mmol) were added under ice bath, the reaction was carried out by heating in an oil bath at 70℃for 8 hours, TLC was checked for progress of the reaction, saturated aqueous sodium bicarbonate solution was added to adjust pH to 8, extraction was carried out with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was recovered by rotary evaporation. Column chromatography purification isolation (P/e=2/1) gave 15.8g (yield: 62.2%) of the yellow oily product. ESI-MS m/z 338.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.80(s,1H),8.31(s,1H),7.42–7.36(m,3H),3.76-3.70(m,1H),3.42-3.35(m,1H),3.22-3.15(m,1H),1.17–1.09(m,6H),1.02(td,J＝7.1,5.0Hz,3H).
Step 4 tert-butyl 2- (5- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate (1-4)
The above intermediate 1-3 (15.7 g,45.6 mmol) was dissolved in isopropanol and DIPEA (16.3 ml,91.3 mmol), 2, 7-diazaspiro [3.5] was added]Nonane-7-carboxylic acid tert-butyl ester (11.6 g,50.2 mmol), heating to 70deg.C for 16h, TLC detection of the reaction was completed, dilution with water, extraction with ethyl acetate, drying of the organic layer with anhydrous sodium sulfate, filtration, and recovery of the solvent by rotary evaporation gave 23.2g of crude yellow oil (yield: 93.5%). ESI-MS m/z 528.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.28(s,1H),7.73(s,1H),7.34–7.20(m,2H),7.03(dd,J＝8.9,4.4Hz,1H),3.90–3.81(m,4H),3.77-3.70(m,1H),3.43-3.37(m,1H),3.26-3.16(m,5H),1.66-1.62(m,4H),1.38(s,9H),1.19–0.96(m,9H).
Step 5- ((4- (2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-5)
The above intermediate 1-4 (22.1 g,41 mmol) was dissolved in dichloromethane (400 ml), trifluoroacetic acid (30 ml) was added, the reaction was carried out at room temperature for 2h, the completion of the reaction was detected by LC/MS, the pH was adjusted to 8-9 with saturated sodium carbonate solution, washing with saturated brine, extraction with additional dichloromethane, drying the organic layer with anhydrous sodium sulfate, filtration, and rotary evaporation to recover the solvent to give 18.6g of crude yellow oil, which was directly used in the next step. ESI-MS m/z 428.2[ M+H ]] + 。
Step 6((1 r,4 r) -4- ((2- (5- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) cyclohexyl) carboxylic acid tert-butyl ester (1-6)
Methyl (1 r,4 r) -4- ((t-butoxycarbonyl) amino) cyclohexyl) -4-methylbenzenesulfonate (33.4 g,85.4 mmol), potassium carbonate (15.0 g,106.8 mmol) and potassium iodide (0.72 g,4.3 mmol) as intermediates 1-5 (18.6 g,42.6 mmol) were dissolved in acetonitrile and reacted at 80℃for 12 hours. After completion of the LC/MS detection reaction, the reaction mixture was washed with saturated brine, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was recovered by rotary evaporation, followed by purification and separation by column chromatography (D/M=20/1) to obtain 13.6g (yield: 48.4%) of a product. ESI-MS m/z 639.2[ M+H ]] + 。
Step 7- ((4- (7- (((1 r,4 r) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropyl benzamide (1-7)
The above intermediate 1-6 (13.2 g,20.3 mmol) was dissolved in dichloromethane (400 ml), trifluoroacetic acid (15 ml) was added, the reaction was carried out at room temperature for 2h, the completion of the reaction was detected by LC/MS, the pH was adjusted to 8-9 with saturated sodium carbonate solution, the mixture was washed with saturated brine, extraction was carried out with additional dichloromethane, the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was recovered by rotary evaporation to give 10.8g of crude yellow oil, which was directly used in the next step. ESI-MS m/z 539.3[ M+H ]] + 。
Step 8N-Ethyl-5-fluoro-N-isopropyl-2- ((4- (7- (((1 r,4 r) -4- (pyrroline-1-sulfonylamino) cyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) benzamide (1)
The above intermediate 1-7 (220 mg,0.40 mmol) and triethylamine (0.15 mL,1.0 mmol) were dissolved in anhydrous dichloromethane, and pyrroline-1-sulfonyl chloride (138 mg,0.80 mmol) was added dropwise under stirring and cooled in an ice bath, followed by reaction at room temperature for 12 hours. After the LC/MS detection reaction, saturated brine is added for quenching, washing, dichloromethane extraction is carried out, anhydrous sodium sulfate is added for drying an organic layer, filtering is carried out, solvent is recovered by rotary evaporation, medium-pressure preparation (fiash) is carried out for purification and separation, and 92.0mg (yield: 33.2%) of a product is obtained. ESI-MS m/z 672.3[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.23(s,1H),7.68(s,1H),7.20(dd,J＝9.1,6.9Hz,2H),7.16(m,1H),6.99(d,J＝6.7Hz,1H),3.83(m,4H),3.79(m,1H),3.34(m,2H),2.95(m,1H),2.85-2.67(m,4H),2.39(d,J＝6.2Hz,2H),2.21(m,4H),1.97(d,J＝7.0Hz,2H),1.93–1.84(m,4H),1.73(m,2H),1.66(m,4H),1.26–1.15(m,4H),1.14(m,7H),0.95(m,3H).
Example 2N-Ethyl-5-fluoro-N-isopropyl-2- ((4- (7- (((1 r,4 r) -4- (piperidine-1-sulfonylamino) cyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) benzamide (2)
Reference example 1, the intermediate 2- ((4- (7- (((1 r,4 r) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [ 3.5) was prepared]Nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropylbenzamide (1-7) was reacted with piperidine-1-sulfonyl chloride and purified by the procedure described in example 1. ESI-MS: m/z=686.3 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.24(s,1H),7.68(s,1H),7.20(dd,J＝9.0,6.7Hz,2H),7.17(m,1H),6.96(m,1H),3.81(s,4H),3.72(m,1H),3.36(m,2H),2.94(m,1H),2.86-2.77(m,4H),2.32(m,2H),2.23(m,4H),1.96(m,2H),1.90(m,4H),1.70(m,2H),1.64-1.50(m,6H),1.28–1.18(m,4H),1.14-0.93(m,10H).
Example 3 2- ((4- (7- (((1 r,4 r) -4- (acridine-1-sulfonylamino) cyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropylbenzamide (3)
Reference example 1, the intermediate 2- ((4- (7- (((1 r,4 r) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [ 3.5) was prepared]Nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropyl-benzamide (1-7) was reacted with acridine-1-sulfonyl chloride and purified by the procedure described in example 1. ESI-MS: m/z=658.3 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.22(s,1H),7.68(s,1H),7.20(m,2H),7.16(m,1H),6.97(d,J＝6.6Hz,1H),3.80(m,4H),3.78(m,1H),3.35-3.18(m,4H),3.31(m,2H),2.92(m,1H),2.29(d,J＝6.4Hz,2H),2.20(m,4H),2.14(m,2H),1.92(d,J＝7.0Hz,2H),1.72(m,2H),1.65(m,4H),1.25-1.14(m,4H),1.13(m,7H),0.88(m,3H).
Example 4 2- ((4- (7- (((1 r,4 r) -4- (3-cyano-acridine-1-sulfonylamino) cyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropylbenzamide (4)
Reference example 1, the intermediate 2- ((4- (7- (((1 r,4 r) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [ 3.5) was prepared]Nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropyl-benzamide (1-7) was reacted with 1-chlorosulfonyl-3-cyanocyclobutane and purified by the procedure described in example 1. ESI-MS: m/z=683.3 [ M+H ]] + ；
Example 5N-Ethyl-5-fluoro-2- ((4- (7- (((1 r,4 r) -4- ((3-fluoro-acridine) -1-sulfonylamino) cyclohexyl) methyl) -diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -isopropylbenzamide (5)
Reference example 1, the intermediate 2- ((4- (7- (((1 r,4 r) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [ 3.5) was prepared]Nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropyl-benzamide (1-7) was reacted with 3-fluoro-acridine-1-sulfonyl chloride and purified by the procedure described in example 1. ESI-MS: m/z=676.3 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.23(s,1H),7.67(s,1H),7.21(dd,J＝8.9,6.7Hz,2H),7.19(m,1H),6.99(d,J＝6.6Hz,1H),3.98(m,1H),3.81(m,4H),3.76(m,1H),3.65-3.58(m,4H),3.34(m,2H),2.91(m,1H),2.28(d,J＝6.4Hz,2H),2.19(m,4H),1.93(d,J＝7.0Hz,2H),1.70(m,2H),1.63(m,4H),1.24-1.14(m,4H),1.12-0.92(m,10H).
Example 6N-Ethyl-5-fluoro-2- ((4- (7- (((1R, 4R) -4- (((R) -3-fluoro-pyrroline) -1-sulfonylamino) cyclohexyl) methyl) -diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -isopropylbenzamide (6)
Reference example 1, the intermediate 2- ((4- (7- (((1 r,4 r) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [ 3.5) was prepared]Nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropyl-benzamide (1-7) was reacted with (R) -3-fluoropyrrolidine-1-sulfonyl chloride and purified by the procedure described in example 1. ESI-MS: m/z=690.3 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.24(s,1H),7.67(s,1H),7.21(dd,J＝9.0,6.9Hz,2H),7.16–7.11(m,1H),6.98(d,J＝6.6Hz,1H),3.84(m,4H),3.78(m,1H),3.40(m,1H),3.33(m,2H),2.96-2.82(m,5H),2.40(d,J＝6.4Hz,2H),2.24(m,4H),1.98(d,J＝7.0Hz,2H),1.84(m,2H),1.71(m,2H),1.62(m,4H),1.26–1.13(m,11H),0.95(m,3H).
Example 7N-Ethyl-5-fluoro-N-isopropyl-2- ((4- (7- (((1 r,4 r) -4- ((4-methylpiperazine) -1-sulfonylamino) cyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) benzamide (7)
Reference example 1, the intermediate 2- ((4- (7- (((1 r,4 r) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [ 3.5) was prepared]Nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropyl-benzamide (1-7) was reacted with 4-methyl-1-piperazine sulfonyl chloride and purified by the procedure described in example 1. ESI-MS: m/z=701.3 [ M+H ]] + ；
Example 8 2- ((4- (7- (((1 r,4 r) -4- ((3, 3-difluoropyrroline) -1-sulfonylamide) cyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropylbenzamide (8)
Reference example 1, the intermediate 2- ((4- (7- (((1 r,4 r) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [ 3.5) was prepared]Nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropyl-benzamide (1-7) was reacted with 3, 3-difluoropyrroline-1-sulfonyl chloride and purified by the procedure described in example 1. ESI-MS: m/z=708.2 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.23(s,1H),7.68(s,1H),7.20(dd,J＝9.1,6.8Hz,2H),7.17–7.11(m,1H),6.99(d,J＝6.6Hz,1H),3.82(m,4H),3.76–3.60(m,1H),3.48(t,J＝13.2Hz,2H),3.34(t,J＝7.3Hz,2H),3.25(s,2H),2.98(s,1H),2.39(m,2H),2.21(br-s,4H),1.99(d,J＝7.0Hz,2H),1.93–1.84(m,2H),1.73(d,J＝13.2Hz,2H),1.66(t,J＝5.2Hz,4H),1.26–1.15(m,6H),1.14-0.98(m,6H),0.85(m,2H).
Example 9N-Ethyl-5-fluoro-N-isopropyl-2- ((4- (7- (((1 r,4 r) -4- ((3-methylpyrrolidine) -1-sulfonylamide) cyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) benzamide (9)
Reference example 1, the intermediate 2- ((4- (7- (((1 r,4 r) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [ 3.5) was prepared]Nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropyl-benzamide (1-7) was reacted with 3-methylpyrroline-1-sulfonyl chloride and purified by the procedure described in example 1. ESI-MS: m/z=686.2 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.24(s,1H),7.67(s,1H),7.20(dd,J＝9.0,6.8Hz,2H),7.18(m,1H),6.98(d,J＝6.6Hz,1H),3.82(s,4H),3.78(m,1H),3.34(m,2H),2.91(m,1H),2.84-2.62(m,4H),2.37(d,J＝6.2Hz,2H),2.20(m,4H),1.98(d,J＝7.0Hz,2H),1.74(m,2H),1.67-1.41(m,7H),1.26–1.19(m,4H),1.14-1.09(m,7H),0.95-0.87(m,6H).
Example 10- ((4- (7- (((1 r,4 r) -4- ((3, 3-difluoroazetidinyl) -1-sulfonylamino) cyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropylbenzamide (10)
Reference example 1, the intermediate 2- ((4- (7- (((1 r,4 r) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [ 3.5) was prepared]Nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-5-fluoro-N-isopropyl-benzamide (1-7) was reacted with 3, 3-difluoroazetidine-1-sulfonyl chloride and purified by the procedure described in example 1. ESI-MS: m/z=694.3 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.24(s,1H),7.68(s,1H),7.21(dd,J＝9.0,6.8Hz,2H),7.18–7.12(m,1H),6.98(d,J＝6.6Hz,1H),3.92-3.87(m,4H),3.81(s,4H),3.77(m,1H),3.32(m,2H),2.91(m,1H),2.28(m,2H),2.20(m,4H),1.93(d,J＝7.0Hz,2H),1.71(m,2H),1.64(m,4H),1.26-1.17(m,4H),1.10-1.03(m,7H),0.97(m,3H).
Example 11- ((4- (7- (((1 r,4 r) -4- ((3, 3-difluoropyrroline) -1-sulfonylamino) cyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-N-isopropylthiophene-2-carboxamide
Synthetic route
Step 1-3-methoxythiophene-2-carboxylic acid methyl ester
3-Hydroxythiophene-2-carboxylic acid methyl ester (7.91 g,50.01 mmol) was dissolved in 100mL of acetone, and potassium carbonate was added(20.70 g,150.00 mmol) and methyl iodide (21.15 g,150.00 mmol) were reacted at 50℃for 16h after TLC detection (PE/EA=10/1), acetone was dried by spin, 50mL of water was added, 100mL of ethyl acetate was extracted three times, and the organic phases were combined, dried over anhydrous sodium sulfate, and dried by spin to give (6.51 g, 75.31%) as a white solid. LC/MS 173.0[ M+H ]] + 。
Step 2:3-methoxythiophene-2-carboxylic acid
Methyl 3-methoxythiophene-2-carboxylate (6.51 g,37.85 mmol) was dissolved in a mixed solvent of 50mL of methanol and 10mL of water, potassium hydroxide (4.86 g,86.78 mmol) was added and reacted at 60℃for 3h.TLC detection (PE/EA=10/1) was completed, methanol was dried by spinning, 2N hydrochloric acid solution was added to adjust pH to 3-4 until a large amount of white solid was precipitated, and filtration was carried out, and 50mL of toluene was added with water to give (5.51 g, 91.97%) white solid. LC/MS 159.0[ M+H ]] + 。
Step 3:N-Ethyl-N-isopropyl-3-methoxythiophene-2-carboxamide
3-methoxythiophene-2-carboxylic acid (5.51 g,34.87 mmol) was dissolved in 75mL of dichloromethane, N, N-diisopropylethylamine (6.75 g,52.31 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (15.90 g,41.84 mmol) were added and reacted at room temperature with stirring for 0.5h N-ethylpropane-2-amine (6.07 g,69.74 mmol) was added and reacted at 25℃for 16h after TLC detection (PE/EA=3/1) was complete, dried by spin-on, column chromatography (P/E=8/1-2/1) to give (5.11 g, 63.01%) as a pale yellow oil. LC/MS 228.1[ M+H ]] + 。
Step 4N-ethyl-3-hydroxy-N-isopropylthiophene-2-carboxamide
N-ethyl-N-isopropyl-3-methoxythiophene-2-carboxamide (5.11 g,22.51 mmol) was dissolved in 10mL of hydroiodic acid solution and reacted at 100℃for 6h, TLC detection (PE/EA=3/1) was completed, saturated sodium bicarbonate solution was added to adjust pH=7, 50mL of dichloromethane was used for extraction three times, the organic phases were combined, dried by spin, column chromatography (P/E=8/1 to 2/1) to give (4.51 g, 93.96%) as a pale yellow oil. LC/MS 214.1[ M+H ]] + 。
Step 5N-ethyl-N-isopropyl-3- (pyrimidine-5-yloxy) thiophene-2-carboxamide
N-ethyl-3-hydroxy-N-isopropylthiophene-2-carboxamide (1.79 g, 8.35)mmol) 5-bromopyrimidine (3.98 g,25.05 mmol), cesium carbonate (8.16 g,25.05 mmol) was dissolved in anhydrous DMF, reacted at 130 ℃ for 16h.tlc detection (P/e=2/1) was complete, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spun-dried, column chromatographed (P/e=8/1-2/1) to give (1.21 g, 49.59%) as a white solid. LC/MS 292.1[ M+H ]] + 。
Step 6 5- ((2- (ethyl (isopropyl) carbamoyl) thiophen-3-yl) oxo) pyrimidine-1-oxide
N-ethyl-N-isopropyl-3- (pyrimidine-5-yloxy) thiophene-2-carboxamide (1.21 g,4.14 mmol) was dissolved in anhydrous dichloromethane, m-CPBA (2.86 g,15.5 mmol) was added under ice bath, reacted overnight at room temperature, the reaction solution was washed once with saturated sodium sulfite solution, twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and spun dry as detected by LC/MS. A yellow oil (0.96 g, 98%) was obtained. LC/MS 308.1[ M+H ]] +
Step 7:3- ((4-chloropyrimidin-5-yl) oxo) -N-ethyl-N-isopropylthiophene-2-carboxamide
5- ((2- (Ethyl (isopropyl) carbamoyl) thiophen-3-yl) oxy) pyrimidine-1-oxide (0.96 g,3.13 mmol) was dissolved in chloroform, triethylamine (0.65 ml,4.69 mmol) was added under ice-bath, phosphorus oxychloride (0.5 ml,5.32 mmol) was reacted at 70℃for 8 hours, TLC detection was completed, saturated sodium bicarbonate solution was added to adjust pH to 8, extraction was performed with ethyl acetate, dried over anhydrous sodium sulfate, filtered and dried by spinning. PTLC (P/e=2/1) gave (0.450 g, 45.0%) as a yellow oil. LC/MS 326.1[ M+H ]] +
Step 8 tert-butyl 2- (5- ((2- (ethyl (isopropyl) carbamoyl) thiophen-3-yl) oxo) pyrimidin-4-yl) -diazaspiro [3.5] nonane-7-carboxylate
3- ((4-Chloropyrimidin-5-yl) oxo) -N-ethyl-N-isopropylthiophene-2-carboxamide (0.15 g,0.46 mmol) was dissolved in isopropanol, DIPEA (0.162 ml,0.93 mmol) was added, 4-aminopiperidine-1-carboxylic acid tert-butyl ester (93 mg,0.46 mmol) was heated to 70℃for 16h, TLC detection reaction was complete, direct spin-dry, PTLC (D/M=20/1) gave (0.25 g, 99.1%) as a yellow oil. LC/MS 516.2[ M+H ]] +
Step 9- ((4- (2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-N-isopropylthiophene-2-carboxamide
Tert-butyl 2- (5- ((2- (ethyl (isopropyl) carbamoyl) thiophen-3-yl) oxo) pyrimidin-4-yl) -diazaspiro [3.5]Nonane-7-carboxylate (0.25 g,0.46 mmol) was dissolved in dichloromethane (4 ml), trifluoroacetic acid (2 ml) was added, reacted at room temperature for 2h, and the reaction was detected by LC/MS and dried directly. A yellow oil was obtained and used directly in the next step. LC/MS 416.2[ M+H ]] +
1 H NMR(400MHz,DMSO-d 6 )δ8.69(d,J＝6.8Hz,1H),8.20(s,1H),7.63(s,1H),6.35(d,J＝7.6Hz,1H),3.92(s,4H),3.78–3.60(m,1H),3.15-3.08(m,2H),2.87-2.77(m,4H),2.03-1.98(m,1H),1.58(t,J＝5.6Hz,4H),1.12-0.98(m,7H),0.86(q,J＝12.5Hz,2H).
Step 10 tert-butyl (1 s,4 s) -4- ((2- (5- ((2- (ethyl (isopropyl) carbamoyl) thiophen-3-yl) oxy) pyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonan-7-yl) methyl) cyclohexyl) carbamate
3- ((4- (2, 7-diazaspiro [3.5 ])]Nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-N-isopropylthiophene-2-carboxamide (0.19 g,0.46 mmol), ((1 r,4 r) -4- ((tert-butoxycarbonyl) amino) cyclohexyl) 4-methylbenzenesulfonic acid methyl ester (533 mg,1.38 mmol), potassium carbonate (284 mg,2.76 mmol), potassium iodide (7 mg,0.046 mmol) were dissolved in acetonitrile and reacted at 80℃for 16h. The reaction was checked by LC/MS, the inorganic salt was filtered, washed twice with dichloromethane, dried by spin-drying and PTLC (D/m=20/1). A yellow oil (0.145 g, 50.4%) was obtained. LC/MS 627.3[ M+H ]] +
Step 11- ((4- (7- (((1 s,4 s) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-N-isopropylthiophene-2-carboxamide
Tert-butyl (1 s,4 s) -4- ((2- (5- ((2- (ethyl (isopropyl) carbamoyl) thiophen-3-yl) oxo) pyrimidin-4-yl) -2, 7-diazaspiro [3.5]Nonan-7-yl) methyl) cyclohexyl carbamate (0.145 g,0.23 mmol) was dissolved in dichloromethane (4 ml), dioxane hydrochloride (2 ml) was added, reacted at room temperature for 2h, and the reaction was detected by LC/MS and directly spin-dried. A yellow oil was obtained and used directly in the next step. LC/MS 527.3[ M+H ]] +
Step 12- ((4- (7- (((1 r,4 r) -4- ((3, 3-difluoropyrrolidine) -1-sulfonylamino) cyclohexyl) methyl) -2, 7-diazaspiro [3.5] nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-N-isopropylthiophene-2-carboxamide
3- ((4- (7- (((1 s,4 s) -4-aminocyclohexyl) methyl) -2, 7-diazaspiro [ 3.5)]Nonan-2-yl) pyrimidin-5-yl) oxo) -N-ethyl-N-isopropylthiophene-2-carboxamide (0.121 g,0.23 mmol) was dissolved in anhydrous dichloromethane (2 ml), triethylamine (0.2 ml,1.38 mmol), 3-difluoropyrrolidine-1-sulfonyl chloride (76 mg,0.37 mmol) was added, reacted at room temperature for 16h, LC/MS detection was complete, direct spin-dry, flash reverse phase preparation, lyophilization to give (78 mg, 52%) colorless oil. LC/MS 696.3[ M+H ]] +
1 H NMR(400MHz,DMSO-d 6 )δ8.69(d,J＝6.8Hz,1H),8.20(s,1H),7.63(s,1H),6.95(d,J＝5.6Hz,1H),6.35(d,J＝7.6Hz,1H),3.92(s,4H),3.78–3.60(m,1H),3.43(t,J＝12.2Hz,2H),3.31(t,J＝7.5Hz,3H),3.25(s,2H),2.97(s,1H),2.36(tt,J＝14.2,7.1Hz,2H),2.22(t,J＝5.5Hz,4H),2.03(d,J＝7.2Hz,2H),1.92–1.84(m,2H),1.72(d,J＝12.8Hz,2H),1.68(t,J＝5.4Hz,4H),1.28–1.16(m,4H),1.12-0.98(m,7H),0.86(q,J＝12.5Hz,2H).
The preparation of the other examples was completed with reference to the preparation methods of examples 1 to 11.
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Biological embodiment
Test example 1 cell experiment (MV 4-11 cell proliferation inhibition experiment)
Determination of cell viability by CCK-8 reagent
The first day: cell plating
1) MV4-11 cell suspension in the flask was collected into a 15mL centrifuge tube, and the cell suspension was centrifuged at 1000rpm for 4min.
2) The supernatant from the centrifuge tube was discarded, and an appropriate amount of fresh complete medium (IMDM+10% FBS+1% P/S) was added to resuspend the cells. mu.L of cell fluid was taken and added to 20. Mu.L of trypan blue and counted.
3) The desired cell suspension volume and complete medium volume were calculated from the viable cell density and the desired number of plated cells. MV4-11 cell plating density of 1X 10 4 100. Mu.L/well.
4) 100. Mu.L of the above cell suspension was pipetted into a 96-well plate using an electric row gun. A blank well was added with 150. Mu.L of complete medium. The perimeter wells of the 96-well plate were filled with an appropriate volume of PBS to prevent evaporation of the liquid. The culture was carried out in a 96-well plate overnight incubator.
The following day: compound formulation
1) The compound of the present application dissolved in DMSO and the positive control SNDX-5613 were removed and subjected to gradient dilution (dilution in a 96-well PCR plate, columns A, B, etc., in order from left to right, to column J).
Column a: initial concentration was 10mM;
column B: diluting 2 mu L A columns of solution into 8 mu L of DMSO to obtain a final concentration of 2000 mu M;
column C: diluting 2 mu L B columns of solution into 8uL of DMSO to obtain a final concentration of 400 mu M;
column D: diluting 2 mu L C columns of solution into 8uL of DMSO to obtain a final concentration of 80 mu M;
column E: diluting 2 mu L D columns of solution into 8uL of DMSO to obtain a final concentration of 16 mu M;
f, column: diluting 2 mu L E columns of solution into 8uL of DMSO to obtain a final concentration of 3.2 mu M;
column G: diluting 2 mu L F columns of solution into 8uL of DMSO to obtain a final concentration of 0.64 mu M;
column H: diluting 2 mu L G columns of solution into 8uL of DMSO to obtain a final concentration of 0.128 mu M;
column I: diluting 2 mu L H columns of solution into 8uL of DMSO to obtain a final concentration of 0.0256 mu M;
j column: diluting 2 mu LI column solution into 8uL DMSO to obtain a final concentration of 0.00512 mu M;
centrifuge at 1000rpm for 1min using a low speed centrifuge.
2) 3 x compound formulation: (96 well cell culture plate dilution)
The final concentrations were obtained in 3. Mu.L to 197. Mu.L of complete medium in columns B-J using a 10. Mu.L manual lance, respectively: 30000 3 x compound solutions at 6000, 1200, 240, 48,9.6,1.92,0.384,0.0768 nm; 3. Mu.L DMSO was used as control in 197. Mu.L of complete medium. The resulting 96-well cell culture plate was shaken at 500rpm for 5 min.
Compound treatment:
1) Using a manual lance, the volume was set at 50. Mu.L, and the prepared 3 Xcompound solutions of each concentration were pipetted into corresponding wells of the 96-well plate after overnight incubation on the first day, and the total incubation volume per well was 150ul. The final concentration of compound in 96 well plates was 10uM,2uM,400nM,80nM,16nM,3.2nM,0.64nM,0.128nM,0.0256nM. The resulting 96-well plate was shaken on a shaker at 500rpm for 10min.
2) Placing the laid 96-well plate into CO 2 Culturing in an incubator for 72 hours.
Results test (fifth day):
1) Using a row gun, the volume was set at 15. Mu.L and CCK-8 assay was added to 96-well cell culture plates at 15. Mu.L/well.
2) Placing 96-well cell culture plate into CO 2 Incubate in incubator for 4 hours.
3) Reading the 450nm absorption value by using an MD enzyme label instrument, calculating the inhibition rate, and calculating the IC by using a GraphPad 50 Values.
The results of cell proliferation experiments for exemplary compounds of the present application are shown in table 1.
Table 1: exemplary Compounds MV4-11 cell proliferation inhibition assay results
The test results show that the compound IC of the application 50 The values are less than 100nM, which indicates that the compounds of the application have good inhibition effect on MV4-11 cells.
Test example 2 test of antitumor drug effect of exemplary Compounds of the present application
The purpose is as follows: the inhibitory effect of the test compounds on growth of subcutaneous transplants in MV4-11 leukemia SCID mice was observed.
The method comprises the following steps: SCID mice were inoculated subcutaneously with MV4-11 cells (5X 10) 6 cell/mouse, 1:1 matrigel), and establishing a MV4-11 mouse transplantation tumor model. The tumor volume to be averaged is about 80 to 120mm 3 Tumor-bearing mice were grouped according to tumor volume by a randomized block method, including solvent control group, positive control group (25 mg/kg), example 8 (25 mg/kg, 50mg/kg, 100 mg/kg), example 10 (25 mg/kg), example 11 (25 mg/kg), and example 12 (25 mg/kg) as test sample groups, which were administered 2 times per day, 8 per group. Each group was administered by gavage, at a volume of 10mL/kg, for 21 days continuously, and the solvent control group was given a blank solvent (0.5% methylcellulose solution). Tumor volumes were measured twice weekly after the start of test drug administration. Animals were euthanized after the end of the experiment.
The results of the in vivo efficacy of exemplary compounds of the present application in animals are shown in table 2 below.
Table 2: exemplary Compounds results of in vivo efficacy experiments in animals
The compound of the embodiment 8 of the application has obvious in-vivo tumor inhibiting activity in each dosage group, and the compound of the embodiment 8 has dose dependency, and the middle and high dosage groups have tumor regression (TGI=100.00%) and the lowest effective dosage is lower than 25mg/kg. Comparing with SNDX-5613 control group, the tumor inhibition effect of the compounds of example 8, example 10, example 11 and example 12 was superior to that of SNDX-5613 control group (P < 0.01) under the condition of the same dose (25 mg/kg, BID) of intragastric administration.
It is to be understood that the foregoing detailed description and accompanying examples are merely exemplary and are not to be considered limiting the scope of the application, which is defined solely by the appended claims and their equivalents. Various alterations and modifications to the disclosed embodiments will be readily apparent to those skilled in the art. Such variations and modifications may be made without departing from the spirit and scope thereof, including but not limited to those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the application. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims (5)

1. A compound of formula Ia or Id, an optical isomer thereof or a pharmaceutically acceptable salt thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
b is selected from C 4- C 8 Cycloalkyl;
l is selected fromWherein, the p end is connected with a pyrimidinyl group, and the Q end is connected with Q;
q is selected from-CH 2 -；
X is selected from-NR x1 R x2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is x1 、R x2 Each independently selected from H, C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl;
rm, rn are independently selected from-OH, F, cl, amino, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, C 1 -C 3 Cyanoalkyl, C 1 -C 3 Hydroxyalkyl or-C (O) NH 2 ；
R 1 、R 2 Each independently selected from H, fluorine, chlorine, bromine, iodine,
n is 1, 2 or 3.
2. A compound or pharmaceutically acceptable salt thereof, as shown below, wherein the compound is selected from the group consisting of:
3. a process for the preparation of a compound according to any one of claims 1 to 2, and optical isomers thereof, comprising the steps of:
(1) Scheme 1:
1) The raw material S1 reacts with the raw material S2 to generate a compound I-1;
2) The compound I-1 is subjected to an oxynitrides reaction to generate a compound I-2;
3) Carrying out halogenation reaction on the compound I-2 to generate a compound I-3;
4) Removing protecting groups after the compound I-3 reacts with the compound PG-L-H to generate a compound I-4;
5) Reacting the compound I-4 with an intermediate M1, and removing Boc protection to obtain an intermediate I-5;
6) Reacting the compound I-5 with a reagent M2 to obtain a compound shown in a formula (I);
wherein PG is a protecting group, LVG is a leaving group, A, B, L, Q, X, rm, rn and n are as defined in any one of claims 1 to 2;
(2) Scheme 2:
the process for preparing compound I-3 is the same as that of scheme 1; the obtained compound I-3 directly reacts with an intermediate M3 to obtain a compound I-5, and then reacts with a reagent M2 to obtain a compound of formula (I);
therein, A, B, L, Q, X, R m 、R n And n is as defined in any one of claims 1 to 2.
4. Use of a compound according to any one of claims 1-2, an optical isomer thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a disease associated with the men-MLL protein.
5. The use according to claim 4, wherein the disease associated with the men-MLL protein comprises mixed leukemia (MLL), MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed leukemia (MLL-r), leukemia associated with MLL rearrangement or MLL gene rearrangement, acute leukemia, chronic leukemia, lymphoblastic leukemia, myelogenous leukemia, childhood leukemia, acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), acute myelogenous leukemia, acute non-lymphoblastic leukemia, chronic Lymphoblastic Leukemia (CLL), chronic Myelogenous Leukemia (CML), treatment-related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), myeloproliferative neoplasia (MPN), plasma cell neoplasm, multiple myeloma, myelodysplasia, cutaneous T cell lymphoma, lymphoid neoplasm, multicellular leukemia, multiple myeloma, or malignant lymphoma.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014164543A1 (en) * 2013-03-13 2014-10-09 The Regents Of The University Of Michigan Compositions comprising thienopyrimidine and thienopyridine compounds and methods of use thereof
WO2015191701A1 (en) * 2014-06-10 2015-12-17 The Trustees Of The University Of Pennsylvania Scaffolds for inhibitors of menin-mll interactions
CN107922378A (en) * 2015-06-04 2018-04-17 库拉肿瘤学公司 For suppressing Multiple Endocrine cancer suppressor protein and the method and composition of the interaction of MLL protein
CN109152784A (en) * 2016-03-16 2019-01-04 库拉肿瘤学公司 The MENIN-MLL inhibitor and application method being substituted
CN109743875A (en) * 2016-06-10 2019-05-10 生命医药公司 The inhibitor of MENIN-MLL interaction

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014164543A1 (en) * 2013-03-13 2014-10-09 The Regents Of The University Of Michigan Compositions comprising thienopyrimidine and thienopyridine compounds and methods of use thereof
WO2015191701A1 (en) * 2014-06-10 2015-12-17 The Trustees Of The University Of Pennsylvania Scaffolds for inhibitors of menin-mll interactions
CN107922378A (en) * 2015-06-04 2018-04-17 库拉肿瘤学公司 For suppressing Multiple Endocrine cancer suppressor protein and the method and composition of the interaction of MLL protein
CN109152784A (en) * 2016-03-16 2019-01-04 库拉肿瘤学公司 The MENIN-MLL inhibitor and application method being substituted
CN109743875A (en) * 2016-06-10 2019-05-10 生命医药公司 The inhibitor of MENIN-MLL interaction

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